Polymorphonuclear leukocytes participate in the mediation of immunologically-induced inflammation and tissue injury in man via interactions with immune complexes (Fc regions of IgG) and components of the complement system (C5a and the opsonic fragment of C3-C3b). Previous work by the applicant has established that such interactions lead not only to selective discharge from leukocytes of pro-inflammatory lysosomal constituents but also to generation and release of oxygen-derived free radicals, prostaglandins and thromboxanes. The applicant has already demonstrated that these leukocyte responses to immunologic stimulioccur independently of phagocytosis, and now proposes to test the hypothesis that they are initiated and can be modulated at the level of the leukocyte plasma membrane. Preliminary studies of ligand (C3b and IgG) binding to human leukocyte surface receptors, redistribution of ligand-receptor complexes, and activation of cell surface enzymes will be expanded so as to determine the roles played by cyclic nucleotides, divalent cations, energy metabolism, microtubules and microfilaments in the regulation of these processes. Concurrently, a major effort will be made to isolate and purify granule and surface membranes from human polymorphonuclear leukocytes. It should be possible, therefore, to determine not only the chemical nature of leukocyte membrane receptors for complement and immunoglobulins but also the subcellular localization of enzymes and substrates involved in the generation of oxygen-derived free radicals (e.g., superoxide anion) and thromboxanes. Finally, the applicant proposes to examine what effects products of "stimulated" leukocytes (particularly oxygen-derived free radicals and thromboxanes) may have on other cell types (e.g., platelets) which are involved in immunologically-induced inflammation and tissue injury. Information derived from these studies may not only provide insight into the pathogenesis of a variety of immunologically-mediated human diseases, but also may provide important clues to more rational forms of therapy.